Download Investigating the genetic and molecular mechanisms underlying

Award ID:
RP160023
Project Title:
Investigating the genetic and molecular mechanisms underlying RAS/ERK
substrate network
Award Mechanism:
Individual Investigator
Principal Investigator:
Arur, Swathi
Entity:
The University of Texas M.D. Anderson Cancer Center
Lay Summary:
The RAS-Extracellular regulated kinase (ERK) pathway is critical for normal animal
development, coordinating different processes like cell division, cell growth, cell death,
and cellfate specification. Alterations in this pathway resulting in too much activity of RAS
or ERK results in multiple types of cancers. ERK in turn, controls the different biological
processes by controlling proteins, which it phosphorylates. These proteins are ERK
targets that need to be phosphorylated to execute specific processes. However, during
excessive ERK activation, some or all of these tissue specific ERK targets are also
inappropriately phosphorylated, and result in mis-regulation of the processes, probably
leading to the disease. These are likely the ‘drivers’ of the disease. Thus, understanding,
when and where these regulators of ERK activity are phosphorylated during normal
development is key to identifying when they come on aberrantly. These thus, form useful
biomarkers for early detection of tumorigenesis. We have already shown that
phosphorylation of these proteins by ERK is conserved in humans, as phosphorylated
Dicer (identified by us as a target of ERK) antibody can be used to detect early stage
endometrial tumors. We propose that understanding the genetic and molecular
mechanisms governing how these phosphorylated proteins function in vivo, in a whole
animal context, independently and together to regulate RAS-ERK dependent events such
as cell growth, cell death and cell divisions is a critical first step to designing fruitful
interventions. In so doing, our studies should accelerate our ability to detect, to treat,
and, hopefully, ultimately to defeat different forms of cancer that are driven by mutations
in oncogenic RAS pathway.